The overall objective of this project is to understand the function of the proteins encoded by the P and MATP genes that are associated with forms of oculocutaneous albinism (OCA2 and OCA4, respectively). The p and Matp proteins are predicted to have 12 membrane-spanning domains and both show homology to transport proteins: p to bacterial and yeast anion transporters and Matp to plant proton/sugar symporters. These proteins may mediate the transport of solutes across the membrane of the melanosome (the melanocyte organelle in which melanin is synthesized and stored) or a precursor vesicle. The two proteins to be studied are encoded by the mouse genes pink-eyed dilution (p) and underwhite (uw) and are defined by several useful mutant alleles. The proposed research has a direct bearing on human health, as OCA2 (tyrosinase-positive oculocutaneous albinism) is one of the most common forms of albinism. OCA2 is especially common among medically underserved populations, including African Americans and Native Americans (e.g., approx. 1 in 250 Hopi or Zuni Indians has OCA2). OCA4 has only recently been described and is caused by mutations in the MATP gene, the human orthologue of underwhite. Like all other forms of albinism, OCA2 and OCA4 are associated with profound changes in the visual system. In past studies, we have cloned or identified both the mouse and human forms of these two genes, and here we propose a new direction of research: to determine the function of their respective proteins using biophysical approaches. An understanding of the function of these proteins will lead to insights into the role of membrane transport mechanisms in melanosome biogenesis and melanin biosynthesis. Disruption of these processes in melanocytes and pigmented retinal epithelial cells leads to albinism and its associated visual system defects. The characterization of mouse models for these hypopigmentation disorders will provide a system to test the efficacy of genetic and biochemical intervention in the treatment of the homologous human disorders. [unreadable] [unreadable]